Selective antagonists of A2A adenosine receptors have proven to be effective for the treatment of Parkinson's disease (PD) both in animal models and in a human trial. However, the initial clinical trial was stopped in phase 3 due to detection of animal toxicity of KW6002. Other investigational compounds lack sufficient potency, selectivity or bioavailability to be considered clinical candidates. This proposal is a phase I SBIR to investigate proprietary novel potent, selective and bioavailable AM blockers for the treatment of PD. It is collaboration between Adenosine Therapeutics, LLC, where medicinal chemistry and compound characterization are conducted, and the Boston University laboratory of Dr. Jiang-Fan Chen, where compounds are investigated in several mouse models of PD. We have already identified one compound, ATL-444, that is very effective in stimulating locomotor activity in a mouse model that is highly predictive of efficacy in PD. There are two specific aims: Aim 1 - Identify another compound, in addition to ATL-444, that is a therapeutic candidate for PD. For this aim, additional compounds will be synthesized and screened, first in radioligand binding assays, and subsequently for locomotor activity in mice. ATL-444 and 1 additional compound will be selected for detailed evaluation in aim 2. Aim 2- Evaluate novel A2A antagonists in four mouse models of PD. These include: A) motor function in normal and dopamine-depleted mice; B) synergistic activity with L-dopa to stimulate motor activity in dopamine-depleted mice; C) attenuation MPTP-induced neurotoxicity by inhibiting MPTP metabolism; and D) delayed L-dopa-induced locomotor sensitization in unilateral 6-OHDA-lesioned mice. We anticipate that we will identify 1 or 2 new clinical candidates for the treatment of PD. Our long-term goal is to bring a new compound into clinical trials. Such a new compound has high therapeutic significance and would be of high commercial value.